Condensation process for preparing pyrimidines



Patented Jan. 30, 1951 CONDENSATION PROCESS FOR PREPARING PYRIMIDINES Thomas E. Bobbins, Pittsburgh, Pa., assignor to Koppers Company, Inc., Pittsburgh, Pa., a corporation of Delaware No Drawing. Application February 10, 1948, Serial No. 7,519

22 Claims. 1

This invention relates to chemical processes and is particularly directed to improvements in processes for condensing ammonium thiocyanate and alpha, beta-unsaturated ketones.

In condensation reactions of this type an inordinately long time is frequently required to obtain the desired yield of product. In other cases, as with certain preformed alpha-, betaunsaturated ketones, yield of the desired product is frequently impaired by reversion of the alpha,beta-unsaturated ketone to its aldol form or its aldol condensable forms.

I have now found that these disadvantages of the prior art may be overcome by Carrying out the condensation of ammonium thiocyanate and an alpha,beta-unsaturated ketone in an inert liquid containing a primary solvent for the alpha,beta-unsaturated ketone which neither gives up nor accepts protons to an appreciable degree and is therefore essentially neutral according to the generalized theory of acids and bases as a predominant ingredient and as a minor ingredient a secondary solvent which is a mutual solvent for ammonium thiocyanate and said pri-- mary solvent, and continuously distilling off the water of formation substantially as it is formed.

In carrying out the reaction in this wise the rate of reaction is substantially increased and where a reversible alpha,beta-unsaturated ketone is a reagent the reverse reaction is retarded or completely inhibited. The inert liquid diluent acts as an entrainer to aid in carrying over the water of formation. By choosing a non-volatile material as the mutual solvent this action is essentially confined to the primary solvent. It is thought, also, that the primary solvent by reason of the fact that it neither gives up nor accepts protons to an appreciable degree tends favorably to modify factors such as acidity and possibly ionic strength which are known to promote the reversion of certain alpha,beta-unsaturated ketones. In any event, by using an inert diluent made up of a predominating amount of a primary solvent for the ketone and a minor amount of a mutual solvent for the primary solvent and ammonium thiocyanate I am able substantially to reduce the time required for the completion of the reaction and/or to obtain markedly improved yields as compared with the prior art processes heretofore available.

The term "neutral solvent or neutral organic solvent is used herein in the same sense that the term aprotic solvent is used by Hall, Chemical Reviews 8, page 193; Glasstone, Text- Book of Physical Chemistry, D. Van Nostrand Co., Inc., New York (1940), page 958; Hammett Physical Organic Chemistry, McGraw-Hill Book Co. (1940), page 288; and, Remick, Electronic Interpretation of Organic Chemistry, John Wiley and Sons, pp. 456-7. Hydrocarbons and halogenated hydrocarbons fall within this class. Any such materials may be used provided suitable provision is made for maintaining a reactive temperature and distilling over the water of formation. If the material is to low boiling, it may be necessary to use superatmospheric pressure to obtain the desired reactive temperature. If it is too high boiling, it may be desirable to include with it a lower lboiling entrainer to help distill over the water. It is most desirable, however, to use materials the atmospheric pressure boiling point of which coincides with the desired reaction temperatures. Low boiling solvents of the benzene series such as benzene, toluene, xylene, ethylbenzene, mono-chlorobenzene and like aprotic solvents of the benzene series are particularly suitable. Those boiling higher than benzene are preferred because the rate of reaction at the temperature which obtains with benzene is undesirably low. All of them are excellent entrainers to aid in distilling off the water of formation. Moreover, they are all immiscible in Water so that which is distilled over with the water is easily recovered for recycling in the process.

In the term mutual solvent the word solvent refers to a liquid which dissolves another substance without any change in chemical constitution Hackhs Chemical Dictionary, third edition. A mutual solvent in the processes of the invention is, therefore, inherently inert insofar as any chemical interaction between the reagents or product of the process is concerned. Conceivably there may be some obscure association between the reagents and/or product and the mutual solvent, and I do not want to exclude such possibility by the use of the term inert, but for practical purposes, there is no interaction which would ordinarily be classed as a chemical reaction as, for example, in the definition of a solvent as a liquid which reacts chemically with a solid and brings it into solution Hackh, supra.

Compounds which are effective mutual solvents in the processes of the invention are, for the most part, those which contain at least one neutral hydrophilic group attached to a neutral organic residue in which there are more than two carbon atoms and for each hydrophilic group less than eight uninterrupted carbon atoms. The term "neutral is used to exclude acidic and basic hydrophilic groups such as carboxyl, sulfo, and amino because both basic and acidic substances are known to promote reversion of alphabets. unsaturated ketones. The terms acidic and basic are used in the classical sense in which acids and bases are substances which ionize in aqueous solution to give hydrogen ions and hydroxyl ions respectively. Typical compounds include the mono-butyl ether of diethylene glycol, the mono-ethyl ether of dipropylene glycol, cyclo hexanol, phenol, isopropyl alcohol, isobutyl alcohol, isoamyl alcohol, mixed amyl alcohols (Pentasol), 2-ethylhexanediol-l,3, and phenylacetonitrile (benzylcyanide) In selecting a suitable mutual solvent, it is generally desirable to avoid the lower molecular weight compounds because of their volatile nature. If the compound is volatile in the reaction mixture it will be continuously distilled over with the water of formation and must be replaced to avoid its depletion in the reaction mixture. If it is also water soluble this replacement, by means of a continuously and automatically operating water trap, is not possible.

It will be understood that whether or not a given mutual solvent is volatile or non-volatile will depend at least in part upon the particular aprotic solvent used. The important thing is this: that the mutual solvent should be nonvolatile in the particular reaction medium involved. Preferably, the mutual solvent should have a boiling point above the boiling point of the reaction mixture, because it is then possible effectively to use a water trap even though the mutual solvent has appreciable water-solubility.

In carrying out processes according to the invention, the reagents are brought together in a suitable reactor in the proportions required for the reaction together with a suitable quantity of the inert diluent. The reaction mixture is then heated to the reaction temperature and su-flicient vapor is withdrawn to carry over the water of formation substantially as it is formed. Additional inert diluent or ingredients thereof may be added to replace that thus withdrawn. In the preferred embodiments of the invention it will be sufficient to effect separation of the water from the entrainer and to return the entrainer to the reaction. 7 Ordinarily this is suitably effected by means of a reflux condenser equipped with a suitable water trap.

The amount of the inert liquid diluent may be varied widely without basically affecting the process. Ordinarily it will be sufficient to use an amount approximately equal to the amount of the reagents. In other words, the inert diluent suitably may be about 50% of the reaction mixture. Smaller quantities down to about of the total content of the reactor may be used without substantially impairing the obtainable yield, but smaller quantities of the diluent are ordinarily undesirable because the reaction mixture tends to thicken up and become dimcult to handle where smaller quantities are employed. Larger quantities also may be used but generally do not give any increase in yield and are uneconomical. In figuring the amount of inert liquid diluent, allowance may be made for any excess ketone over the stoiohiometric proportions of 1 mol alpha,beta-unsaturated ketone for each mol of ammonium thiocyanate because the excess for all intents and purposes is part of the inert liquid diluent. Ordinarily, it will not be necessary or desirable to use more than about the effect of the aprotic solvent.

2 or, at most, about 3 parts of inert diluent for each part of reagents. Thus, in the preferred forms of the invention the inert diluent is desirably kept to around of the reaction mixture though it may, if desired, range from about 30 to about thereof. By reaction mixture, I mean to include all the ingredients charged into the reaction vessel, including the inert diluent.

The amount of mutual solvent may be varied widely provided so much is not used as to destroy the predominant effect of the aprotic solvent. Ordinarily it will be advantageous if the amount of mutual solvent is between about 20 and 35 parts for every parts of the aprotic solvent, figuring in any excess ketone as mutual solvent. Optimum yields are generally obtained within this range. Any smaller quantity may be used, but in general itis not desirable to use less than about 2.5 parts for every 100 parts of aprotic solvent because the effect diminishes as the amount is made smaller and smaller. Larger amounts also may be used. provided the effector the mutual solvent does not predominate over Ordinarily, up to about 50 parts for every 100 parts of aprotic solvent may be used. Those skilled in the art having these factors in mind will readily be able, in view of the specific examples, to determine suitable proportions.

I have also found that still further improved yields may be obtained by using an excess of the reagent ketone. Ammonium thiocyanate condenses with the reagent ketone in the propertions of 3. mol ammonium thiocyanate for each mol of alphabeta-unsaturatecl ketone. By maintaining a slight excess of the reagent ketone it is possible to obtain substantially better yields than with the. stoichiometric proportions or with an excess of ammonium thiocyanate. I have found that satisfactory results are obtained with a 10 or 15% excess of the reagent ketone. More or less than this amount may be used. If too little is used, the eifect is proportionately reduced; and if toomuch is employed, the predominating effect of the aprotic solvent maybe interfered with. Ordinarily it will be sufficient to use between about 2.5 and about 25% excess of the unsaturated ketone.

The processes of the invention are particularly applicable to condensations of ammonium thiccyanate with mesityl oxide because of the particu lar susceptibility of mesityloxide to reversion. Not only is the yield based on mesityl oxide very materially lowered due to reversion of mesityl oxide when the process is carried out in accordance with the prior art, but also the acetone which is formed in the reversion has an adverse efiect upon the velocity of the reaction. If the reaction is carried out under reflux, the effect of the. acetone is to reduce the temperature of the reaction and thus lower its velocity. If the water of formation is continuously distilled over, acetone distills over with the water. Mesityl oxide is also distilled over with the net result that there is a depletion of this particular reagent in the reaction vessel so'that it is not possible tomaintain enough rnesityl oxide therein to effect substantial conversion of the ammonium thiocyanate to the desired product. The invention may be considered particularly applicable therefore to preformed a-lpha, beta-unsaturated ketones Which on reversion give Volatile products such as acetone, methyl ethyl ketone, diethyl ketone and methyl isopr'opyl ketone. Alpha, beta-unsaturated ketones of this type include not only the dehydraldol condensed forms of the simple ketones mentioned in the sense that mesityl oxide is the dehydraldol condensed form of acetone, but also such other alpha, beta-unsaturated ketones as vinyl methyl ketone and benzalacetone.

In its broader aspects, however, the invention is applicable to other preformed alpha, beta-unsaturated ketones as well as to the ketonic reversion products thereof. Apparently when a simple ketone capable of undergoing dehydraldol condensation to an alpha, beta-unsaturated ketone is non-volatile at the temperature required to effect the condensation, satisfactory yields may be obtained starting with either the simple ketone or the preformed alpha-beta-unsaturated ketone derived therefrom. Even with such materials, however, the combined effect of an aprotic solvent and a mutual solvent for the ketone and the ammonium thiocyanate can be expected to increase the velocity of the reaction and thereby make it possible to obtain higher yields in the same period of time.

The invention may be fully understood by reference to the accompanying examples. Parts and percentages as used herein are by weight unless otherwise specified.

EXAMPLE I Into a reactor provided with a reflux condenser connected thereto by a Dean-Stark water trap there was introduced 57.8 parts of ammonium thiocyanate, 81 parts of mesityl oxide, 117 parts toluene and 12 parts cyclohexanol. The water trap has a capacity of 13 parts toluene or 15 parts water. While mechanically agitating the reaction mixture thus obtained, heat was applied as was required to initiate and to maintain a gentle reflux. The reaction was continued for four hours from the beginning of reflux during which time water was periodically drained from the water trap whenever 2 or 3 parts had accumulated therein. 13.0 parts of water were thus obtained. The temperature at the beginning of the refluxing was 107.5 C. and at the end of the reaction was 111 (3. During this period the temperature ranged from a minimum of 107.5 C. to a maximum of 111 C. After cooling, the reaction mixture was diluted with about 100 parts of water and filtered on a centrifuge. The reaction product was then washed on the centrifuge with a further quantity of water and then air dried for at least 24 hours at room temperature. The filter cake weighed 113.4 parts amounting to a 96.7% yield based upon the ammonium thiocyanate.

The process of Example 1 was repeated with the only essential variable being the amount of cyclohexanol. The yields obtained are compared with that of Example I in the following table:

These results show that the addition of cycle hexanol brings about a marked improvement in the yield up to between about 40 and 45 parts of cyclohexanol. It is thus possible to obtain effective increase in yield by using up to about 2 parts of cyclohexanol for every 3 parts of toluene. In other words, using an inert diluent liquid containing up to 40-45% cyclohexanol and the balance toluene.

The procedure of Example I was repeated with.

Table II EFFECT OF EXCESS MESITYL OXIDE Excess (if mesity Cyclohex- Percent Example oxide in anol Yield percent XL None No 73. 2 II 10 No 85.8 None Yes 88.4 5 Yes 93.2 10 Yes 96.8 15 Yes 1 99. 2'

1 Reaction product diluted with 44 parts toluene and allowed tostand overnight and then centrifuged and Washed on the centrifuge with water.

The results illustrated in Table 11 show the marked increase obtainable through the use of excess of mesityl oxide. The marked improvement shown for Example II as compared with Example XI is believed to be due in part to the fact that mesityl oxide is a mutual solvent for ammonium thiocyanate and toluene although this evidently is not the sole efiect of the excess.

The procedure of Example I was repeated using the same proportions with the only essen tial variable being in the kind of mutual solvent except for Examples XVI and XVII where the time was 4.25 hours instead of 4 hours.- The yields obtained are compared with those of Examples I and II in the following table:

(a) Pentasol l. (b) Pentasol (a) Isoamyl alcohol (11) Isoamyl alcohol. (a) DoWano151B (b) Dowanol 51B (a) Isobutyl alcol:ol (h) Isobutyl alcohol. (a) Phenol (I1) Phenol Phcnyl acetonitrile Z-ethylnexanediol-l, 3.

Cyelolicxanol None 1 The mono butyl ether of diethylene glycol sold by the Carbide and Carbon Chemical Co.

M1Xd amyl alcohols sold under this name by the Sharples Co. Mixture of isomeric amyl alcohols obtained by chlorinatiug a mixture of normal pentane and isopentane and followed by hydrolysis. Normalamyl alcohol, Z-methyl butanol and 3-inethyl butanol are the predominant constituents and pentanol-2 and pentanol-3 make up the remainder. The boiling range is ll4 C. to 138 C. and 60% boils Within l20l28 C.

3 The mono ethyl ether of dipiopyleiie glycol sold by the Dow Chemical Co.

In the foregoing examples the time has been maintained at 4 hours throughout in order that a comparison of the results may be made. If the reaction is permitted to run for a longer time, substantially improved yields may be ob;

7 tained. This is illustrated in the following table in which the procedure was that of Example X VI in which the only essential variable was the time.

The data given in Table IV show a, regular increase in yield as the time is increased. They show also that if the time is sufiicent an almost quantitative yield of reaction product is obtainable.

The procedure of the foregoing examples maybe used Without change other than as required in the proportion of the reagents, to affect condensation of ammonium thiocyanate with any nonfugitive dehydraldol condensable ketone such as cyclohexanone, ortho and para-methyl cyclohexanone, 3,5-dimethyl cyclohexanone, alpha tetralone, cyclopentancne, carvone, menthone, acetophenone, phenyl acetone, acetonyl acetone, isophorone, diisopropyl ketone, methyl isobutyl ketone, dipropyl ketone, methyl propyl ketone, methyl butyl ketone, methyl amyl ket-one, methyl hexyl ketone, methyl gamma-hydroxypropyl ketone and methyl beta-hydroxy ethyl ketone as well as the aldols and alpha,beta-unsaturated ketones of these simple ketones. The processes of the examples are also applicable to any of the alpha, beta-unsaturated ketones such as benzal acetone, 3-butene-2-one (vinyl methyl ketone), S-pentene-Z-one and 4--methyl-3-hexene- 2-one. The processes are also applicable to intermediate forms such as diacetone alcohol and diacetone amine, although as a rule the results obtainable with such intermediate products are not as good as with the preformed alpha,beta unsaturated ketones. The processes are also applicable to simple ketones of a volatile nature such as acetone, methyl ethyl ketone and the like, particularly where the temperature is suitably adjusted by use of superatmospheric pres-- sure and loss of ketone in the distillation of water is made up by adding additional amounts.

While I have described my invention with reference to particular embodiments, it will be understood that my invention is not limited to these particular embodiments, but that variation be made therein within the scope of the invention as set forth herein in the appended claims.

I claim:

1. In a process for preparing condensation products of ammonium thiocyanate and an alpha,beta-unsaturated ire-tone, the steps of effecting the condensation in an inert liquid diluent consisting predominantlg. of a neutral organic solvent and containing a mutual solvent for ammonium thiocyanate and said neutral organic solvent and continuously distilling oil" water of formation substantially as it is formed.

2. The method of claim 1 in which the mutual solvent consists predominantly of one or more compounds containing at least one neutral hydrophilic group and a neutral organic residue which contains more than two carbon atoms for each hydrophilic group and less than eight uninterrupted carbon atoms.

'3. In a process for preparing condensation products of ammonium thiocyanate and an alphat,beta-unsaturated ketone, the steps of effecting the, condensation in an inert liquid diluent consisting predominantly of a neutral organicsolvent and containing a non-volatile mutual solvent for ammonium thiocyanate and said neutral organic solvent and continuously distilling off water of formation substantially as it is formed.

4. The method of claim 3 in which the mutual solvent consists predominantly of one or more compounds containing at least one neutral hydrophilic group and a neutral organic residue which contains more than two carbon atoms for each hydrophilic group and less than eight uninterrupted carbon atoms.

5.. The, method of claim 4 in which the hydrophilic group is hydroxy.

6.. The method of claim 5 inwhich the hydroxy group is comprised in a monohydric alcohol.

7. The method of claim 6 in which the organic residue is. hydrocarbon.

8. The method of claim '7 in which the hydrocarbon residue is saturated and contains at least live and not more than six carbon atoms.

9. The method of claim 8 in which the hydrocarbon residue consists of five aliphatic carbon atoms.

10. The method of claim 3 in which the mutual solvent consists predominantly of cyclohexanol.

11. The method of claim 3 in which the mutual solvent consists predominantly of a polyalkyleneglycol monoalkylether.

12. The method of claim 3 in which the polyalkylene glycol monoalkyl ether is diethylenegly' col mono butyl ether.

l3.v In a process for preparing pyrimidines by the condensation of ammonium thiocyanate and an alpha,betaunsaturated ketone, the steps of bringing together ammonium thiocyanate, a preformed alpha,betaunsaturated ketone and an inert liquid diluent consisting predominantly of a neutral organic solvent, and containing a nonvolatile mutual solvent for ammonium thiocyanate and said neutral organic solvent in the proportions of 2.5 to 50 parts of mutual solvent for each 100. parts of a neutral organic solvent, and from 3 to 21 parts of said diluent. for each '7 parts of the reagent, said reagents being in the proportion of 1 mol part or ammonium thiocyanate and 1.025 to 1.25 mol parts of. alpha,beta-unsaturated ketone, heating the reaction mixture thus formed; as required to effect the desired reaction and continuously distilling off water of formation substantially as it is formed.

14. The method of claim 13 in which theneutra-l organic solvent is a low boiling solvent of the benzene series other than benzene.

15. The method of claim 14 in which the mutual solvent consists predominantly of one or more compounds containing at least one neutral hydrophilic group and a neutral organic residue which contains more than two carbon atoms for each hydrophilic group and less than eight uninterrupted carbon atoms.

16 The method of claim 15 in which the alpha,beta-unsaturated ketone is mesityl oxide.

17. The method of claim 13 in which the mutual solvent consists predominantly of cyclohexanol.

I tual solvent consists predominantly ofdi'ethylene glycol monobutyl ether.

20. The method of claim 19 in which the alpha,betaunsaturated ketone is mesityl oxide.

21. The method of claim 13 in which the mutual solvent consists predominantly of amyl a1- cohol.

22. The method of claim 21 in which the alpha,beta-unsaturated ketone is mestiyl oxide.

THOMAS E. ROBBINS.

REFERENCES CITED The following references are of record in the file of this patent:

10 UNITED STATES PATENTS Number Name Date 2,234,848 Ter Horst Mar. 11, 1941 2,264,759 Jones Dec. 2, 1941 5 2,399,650 McAllister et a1. Feb. 2, 1943 OTHER REFERENCES Transactions, Institution of Chemical Engineers, pages 189-198 (1938).

Daniels et a1.: Experimental Physical Chemistry (1941) Edition, pages 154-156.

Sidgwick: Organic Chemistry of Nitrogen (19 12), page 314. 

13. IN A PROCESS FOR PREPARING PYRIMIDINES BY THE CONDENSATION OF AMMONIUM THIOCYANATE AND AN ALPHA, BETA-UNSATURATED KETONE, THE STEPS OF BRINGING TOGETHER AMMONIUM THIOCYANATE, A PREFORMED ALPHA, BETA-UNSATURATED KETONE AND AN INERT LIQUID DILUENT CONSISTING PREDOMINANTLY OF A NEUTRAL ORGANIC SOLVENT, AND CONTAINING A NONVOLATILE MUTUAL SOLVENT FOR AMMONIUM THIOCYANATE AND SAID NEUTRAL ORGANIC SOLVENT IN THE PROPORTIONS OF 2.5 TO 50 PARTS OF MUTUAL SOLVENT, AND EACH 100 PARTS OF A NEUTRAL ORGANIC SOLVENT, AND FROM 3 TO 21 PARTS OF SAID DILUENT FOR EACH 7 PARTS OF THE REAGENT, SAID REAGENTS BEING IN THE PROPORTION OF 1 MOL PART OF AMMONIUM THIOCYANATE AND 1.025 TO 1.25 MOL PARTS OF ALPHA, BETA-UNSATURATED KETONE, HEATING THE REACTION MIXTURE THUS FORMED AS REQUIRED TO EFFECT THE DESIRED REACTION AND CONTINUOUSLY DISTILLING OFF WATER OF FORMATION SUBSTANTIALLY AS IT IS FORMED. 